The activation of cellular oncogenes appears to play a central role in the transformation of normal cells to a neoplastic phenotype. The c-myc oncogene has been implicated in a wide range of tumor cells, especially in B cell neoplasia, and hence is particularly important to study in terms of regulation and function. We have recently found that, when linked to viral promoters, the c-myc gene induces fibroblast cell lines to become tumorigenic in nude mice. This study will be extended to determine if alteration of the c-myc promoter is required for oncogenic activation of the gene, and if there is a threshold level of c-myc expression that is necessary for tumorigenesis. A second study will focus on the influence of c-myc on the expression of other genes, in particular whether c-myc can induce transcription from genes which lack enhancers. A third study will examine the effect of constitutive c-myc expression on the in vitro differentiation of the human promyelocytic leukemia line, HL-60. These experiments will explore the relationship between activated cellular oncogenes and their block in differentiation and continued proliferation of tumor cells. Finally, the biological activity of c-myc retrovirus will be studied, especially the transforming potential in vivo and the effect on primary cells in vitro. A novel DHFR-myc retrovirus that can be amplified in "normal" cells will also be constructed to attempt to identify cellular genes that are influenced by overexpression of c-myc. All of these studies are designed to further our understanding of the c-myc oncogene in cell transformation. (X)